The unique stability, reactivity and biological properties of fluorinated compounds contribute to their widespread use in many chemical disciplines. Compounds containing a trifluoromethyl group have been studied extensively. Compounds containing partially fluorinated alkyl groups, such as a difluoromethyl group, should be similarly valuable for medicinal chemistry because such groups could act as lipophilic hydrogen bond donors and as bio-isosteres of alcohols and thiols (Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626, Meanwell, N. A. J. Med. Chem. 2011, 54, 2529). However, methods for the introduction of a difluoromethyl group are limited, and methods for the introduction of a difluoromethyl group onto arenes are even more limited. Hence there is a current need for new procedures to generate difluoromethylarenes (Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465).
Most current syntheses of difluoromethylarenes require hazardous reagents or multi-step sequences (Scheme 1). Fluoro-deoxygenation of aldehydes with sulfur tetrafluoride or aminosulfurtrifluorides (DAST, Deoxofluor) is the most common route to difluoromethyl compounds. However, these reagents release hydrogen fluoride upon contact with water and may undergo explosive decomposition when heated (Markovski, L. N.; Pahinnik, V. E.; Kirsanov, A. V. Synthesis 1973, 787, Middleton, W. J. J. Org. Chem. 1975, 40, 574). Amii and coworkers recently reported a three-step route to difluoromethylarenes; however, the final step of this process only occurred with electron-deficient aryl iodides, and the three-step process with electron-poor arenes occurred in modest overall yields (Scheme 1) (Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560). Baran recently reported a new reagent that leads to the addition of difluoromethyl radicals to heteroaromatic systems under mild conditions (Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494). However, reactions with arenes were not reported. Thus, methods for the introduction of a difluoromethyl group onto arenes and methods for the introduction of the difluoromethyl group with regioselectivities that complement those resulting from radical-based reactions are needed.
